Pharmacokinetic/pharmacodynamic modelling of effects of dexamethasone and prednisolone in combination with endogenous cortisol on lymphocyte counts and systemic markers of bone turn over and inflammation in healthy and asthmatic men.

OBJECTIVE: To compare potency and efficacy of dexamethasone (DEXA) and prednisolone (PRED) in assumed equipotent doses in combination with endogenous cortisol, using lymphocyte counts, plasma osteocalcin (OC), and eosinophilic cationic protein (ECP) as effect variables and to evaluate potential differences between healthy subjects and asthmatic patients. METHODS: Eight healthy subjects and six asthmatic patients who had stopped taking their regular inhaled glucocorticosteroid treatment (ICS) for 1 week, were given an IV bolus of DEXA and PRED in assumed equipotent doses of 2.0 mg and 12.5 mg, respectively, on separate occasions, in combination with subcutaneously injected granulocyte-colony-stimulating factor (G-CSF) as a stimulant for ECP production. Plasma levels of DEXA, PRED, cortisol and effect variables were determined over 25 h and pharmacokinetic-pharmacodynamic (PK-PD) modelling was performed. RESULTS: Baseline cortisol concentration was lower in patients than in healthy subjects. Both of the exogenous glucocorticoids (GCs) diminished cortisol production. In the healthy subjects, the cortisol production remained suppressed for the full duration of the study day after DEXA but not after PRED. In the asthmatic patients though, the reappearance of the endogenous production of cortisol was seen after both DEXA and PRED. The E(max) values for lymphocyte counts and OC showed that cortisol acted as partial, and DEXA and PRED as full agonists. The observed responses of DEXA and PRED suppressing cortisol, OC and lymphocyte counts were all of the same relative order of magnitude, in accordance with the estimated PD parameters. However, cortisol was estimated to have very little effect on ECP and modelling further predicted that DEXA and PRED were only partial agonists for this effect, without a difference between healthy and asthmatic subjects. Yet, in healthy subjects, the area under the concentration-time curves (AUCs) indicated unexpectedly that ECP was only suppressed after PRED and not after DEXA, while in patients it was suppressed after both GCs. The rank order of potency on lymphocyte counts, OC and ECP was DEXA>PRED>cortisol, although the different relative potencies of the three GCs involved were not the same for all of the three effect variables and differences were also found between healthy and asthmatic subjects. CONCLUSION: PK-PD modelling studies of GCs demonstrated not only differences in potency of DEXA and PRED on the measured systemic markers, but also different potencies per target tissue and differences between healthy and asthmatic men. The effects caused by the achieved blood concentrations of DEXA and PRED, expressed as AUCs of the effect variables, were in accordance with their respective E(max) values in case of the lymphocytes and OC but not for ECP.

Distinct actions of prednisolone and dexamethasone towards osteocalcin and eosinophilic cationic protein in assumed clinically equivalent doses: a study in healthy men.

OBJECTIVE: To study the effects of prednisolone (PRED) and dexamethasone (DEXA) in assumed clinically equivalent doses towards the lowering of cortisol, osteocalcin (OC) and the stimulated rise of eosinophilic cationic protein (ECP) by granulocyte colony stimulating factor (G-CSF). METHODS: At four separate sessions of 25 h each, saline i.v. alone, G-CSF s.c. alone or in combination with either 12.5 mg PRED i.v. or 2.0 mg DEXA i.v., were randomly administered in eight healthy male subjects. RESULTS: All subjects had equal lowering of cortisol after DEXA and PRED at 10 h, whereas a sustained suppression at 25 h persisted only after administration of DEXA. Between 4 h and 10 h after administration of DEXA and PRED, the change in the area under the concentration-time curve (DeltaAUC4-10) of OC became 24.4% and 2.3% lower, respectively ( p<0.0001). After 25 h, this effect persisted for DEXA. DeltaAUC4-10 of the G-CSF-stimulated ECP response decreased by a mean of 76.8% after PRED compared with DEXA and to controls ( p<0.02), and this difference had disappeared at 25 h. DEXA did not elicit any effect towards the G-CSF-stimulated ECP response. CONCLUSION: PRED and DEXA in formerly assumed clinically equivalent doses induced a similar suppression towards cortisol within the first 10 h, but had different actions towards blood concentrations of OC and ECP following G-CSF stimulation in healthy male subjects.

Lack of relationships between cumulative methylprednisolone dose and bone mineral density in healthy men and postmenopausal women with chronic low back pain.

The medical use of glucocorticoids (GCs) is related to low bone mineral density (BMD). In this study we tested the hypothesis that the cumulative dose of GC is not related to BMD outcome. The study was cross-sectional in design and included healthy individuals with chronic low back pain resistant to conventional treatments. In two steroid-naive subjects cortisol and methylprednisolone (MP) concentrations were serially assessed after a single MP depot injection (160 mg epidurally). Furthermore, in 14 men and 14 postmenopausal women, previously treated with multiple epidural MP depots, endocrine parameters were analysed in relation to BMD outcomes. The minimal cumulative MP dose received by all 28 subjects was 3 g. In the two steroid-naive subjects, cortisol concentrations were completely suppressed for at least 6 days and partly recovered over the course of 30 days. During this period, MP concentrations remained detectable in plasma. In the 28 subjects, the cumulative MP dose received was 7.76+/-4.23 g in the men and 8.50+/-3.13 g in the women (mean+/-1SD). None of the men had osteoporosis, but osteopenia was prevalent in 78.5% according to WHO criteria extrapolated to men. Half of the women had osteoporosis and half of them had osteopenia. The body mass index (BMI) and endogenous oestradiol levels of the men were not related to BMD outcomes. Univariate linear relationships in women were found between BMI and spinal ( r 0.62; P=0.02) and total hip BMD ( r 0.61; P=0.03), but not femoral neck BMD. In women, relationships were also found between the total and, for protein binding-corrected oestradiol levels, and spinal BMD ( r 0.70; P=0.01 and r 0.72; P=0.01, respectively) and total hip BMD ( r 0.53; P=0.08 and r 0.56; P=0.05, respectively). No significance was observed between endogenous oestradiol levels and the BMD of the femoral neck. The administration of a single MP depot injection (160 mg) resembled a systemic low peak dose GC exposure. The administration of multiple MP depots in men and women with chronic low back pain revealed no relationship between cumulative GC dose and BMD. These findings support the hypothesis of a non-existent relationship between cumulative GC dose and BMD outcomes in healthy men and women with a prior GC administration of at least 3 g.

Bronchodilating effects of cumulative doses of formoterol from a novel multi-dose inhaler (Airmax).

The bronchodilating properties of formoterol from a novel multi-dose inhaler, Airmax 6 microg and from a single-dose dry powder inhaler Foradil Aeroliser 12 microg were investigated in 31 adult asthmatics with FEV1 > or = 60% predicted and a reversibility > or = 12%. Patients received on a single day four doses of formoterol: cumulative dose 6, 12, 24 and 48 microg from Airmax, or 12, 24, 48 and 96 microg from Aeroliser. The mean FEV1 (SD) from baseline to 1 h after the final cumulative dose increased by 0.81 l from 2.62 (0.58) to 3.43 l (0.70) with Airmax and by 0.85 l from 2.65 (0.60) to 3.5 l (0.68) with Aeroliser. All 90% CIs for all four dose comparisons were within the equivalence range +/- 0.11. There was a higher incidence of hypokalaemia and hyperglycaemia at highest doses during treatment with the Aeroliser than with Airmax. In conclusion, formoterol delivered from Airmax provides a dose-dependent bronchodilating effect which is similar to that obtained by Aeroliser, at double the dose.

Comparison of quantitative ultrasound parameters with dual energy X-ray absorptiometry in pre- and postmenopausal women.

BACKGROUND: Quantitative ultrasound (QUS) has been claimed as an alternative technique for risk assessment of hip fractures associated with osteoporosis. However, reports concerning modest correlations between QUS parameters and dual energy X-ray absorptiometry (DXA) in women raise questions about the reliability of QUS technology to predict bone mineral density (BMD). Partially, the lack of stronger correlations may be due to heterogeneity in bone architecture deterioration which may be more pronounced in older than in younger women. Therefore, it was thought important to study QUS/DXA interrelationships in subgroups of pre- and postmenopausal women. METHODS: We studied 217 pre- and postmenopausal women between the ages of 25 and 75 years, who were referred for a BMD measurement because of osteoporosis in at least one family member either in the first or in the second degree. All women had a calcaneal QUS and a DXA measurement at the lumbar spine, total hip and femoral neck. RESULTS: The linear regression coefficients between the QUS parameters broadband ultrasound attenuation (BUA) and speed of sound (SOS) and DXA at the various sites in the group as a whole were 0.53 to 0.54 (P<0.0001). Significantly lower regression coefficients between BUA and DXA at the total hip and the femoral neck were found in premenopausal women (r=0.31 and 0.38, P<0.0001) compared to postmenopausal women (r=0.56 and 0.53, P<0.0001). For SOS there was no significant difference between the regression coefficients in the pre- and postmenopausal group. The overall prevalence of osteoporosis as assessed by DXA in the total group was 25% (6% in the pre- and 36% in the postmenopausal group). BUA failed to detect osteoporosis in all five premenopausal women but also in 20 out of 50 postmenopausal women with osteoporosis according to DXA measurements. SOS measurements were even worse in this respect. CONCLUSIONS: Linear regression coefficients between calcaneal QUS parameters and DXA are only modest considering a group of 25--75-year-old Dutch women. In the subgroup of premenopausal women correlations between BUA and BMD at the hip and femoral neck are worse compared to those in postmenopausal women. The predictive value of QUS parameters for BMD is limited, therefore it is not appropriate to use QUS as a surrogate for DXA.